JP5713544B2 - Imidafenacin-containing intraoral rapidly disintegrating tablets - Google Patents

Description

  The present invention relates to an intraoral quick-disintegrating tablet containing imidafenacin as an active ingredient.

Imidafenacin is a compound having a muscarinic receptor M3 and M1 antagonistic action (Patent Document 1) and is provided as a therapeutic agent for overactive bladder (Non-Patent Document 1). As pharmaceutical formulations containing imidafenacin as a main component, oral solid preparations containing imidafenacin, transdermal absorption agents, and the like are known (Patent Documents 2 and 3).
Patent Document 2 describes that imidafenacin preparations are unstable to light, so that light stabilization is achieved by coating tablets with a coating solution containing titanium oxide and iron sesquioxide.
Patent Documents 3 and 4 disclose sustained-release oral preparations. However, it is not known to incorporate aminoalkyl methacrylate copolymer E or tocopherol in the imidafenacin granulation.

  On the other hand, for the purpose of improving QOL (Quality of Life) of patients, formulation development with pharmacological ingenuity has been actively conducted, and intraoral rapidly disintegrating tablets are the most frequently developed formulations. Intraoral rapidly disintegrating tablets are easy to take because even a small amount of saliva in the mouth disintegrates instantly, and are the best preparations for the elderly and children who are difficult to swallow with ordinary tablets. Moreover, since it can be taken without water, it has the advantage that the place and time for taking are not limited.

  However, it is difficult to coat the tablet with titanium oxide / iron sesquioxide while maintaining the disintegration property, and there has been no report on a light-stable imidafenacin-containing intraoral quick-disintegrating tablet.

JP-A-7-215943 WO01 / 34147 A1 brochure WO2005 / 011682 A1 brochure WO2006 / 0808481 A1 brochure

Bioorg. Med. Chem., 1999, Vol. 7, 1151-1161

  The present invention provides an imidafenacin-containing intraoral quick-disintegrating tablet that is excellent in light stability and has few manufacturing process degradation products.

The present inventors have found that light stability is improved by granulating imidafenacin and coating it with a non-cellulosic coating agent (PCT / JP2009 / 51651).
However, in this granulation and coating process, a problem that a decomposition product of imidafenacin, which is an active ingredient, occurs. Therefore, studies have been made to reduce the decomposition products, and the present invention has been completed.

  That is, the present invention covers a granule obtained by granulating one or more selected from the group consisting of tocopherol, a tocopherol derivative and an acrylic polymer together with imidafenacin with a non-cellulosic coating agent, and compression molding. The present invention relates to an intraoral quick disintegrating tablet.

  According to the present invention, it is possible to provide an imidafenacin-containing intraoral rapidly disintegrating tablet which is excellent in oral disintegration and light stability and has few manufacturing process degradation products in a tablet.

  Hereinafter, the present invention will be described in detail. In the present specification, an intraoral quick-disintegrating tablet means, in the presence of saliva in the oral cavity, about 90 seconds without chewing, preferably about 60 seconds, more preferably from 40 seconds. A solid pharmaceutical preparation that disintegrates in a short time.

  Imidafenacin, which is an active ingredient used in the intraoral quick-disintegrating tablet of the present invention, is 4- (2-methyl-1-imidazolyl)-, which is a therapeutic agent for pollakiuria and urinary incontinence having a selective anticholinergic action on the bladder. 2,2-diphenylbutyramide.

Examples of the tocopherol or tocopherol derivative include dl-α-tocopherol (vitamin E), d-σ-tocopherol, tocopherol acetate, tocopherol phosphate, tocopherol sulfate, tocopherol glycosyl ester and salts thereof. The content of tocopherol is preferably 0.005% by mass or more, more preferably 0.01% by mass or more, more preferably 0.05 to 10% by mass, particularly preferably 0.08 to 5% by mass in the imidafenacin-containing granule. %.

  Acrylic polymers are acidic polymers (which contain carboxyl groups in monomer units and are mainly used for enteric coating), neutral polymers (those that contain methacrylate esters in monomer units and have high film permeability). Mainly used for sustained-release preparations) and basic polymers (containing amino groups in monomer units and mainly used for gastric coating). Examples of acrylic polymers include ethyl acrylate / methyl methacrylate copolymer, aminoalkyl methacrylate copolymer E, aminoalkyl methacrylate copolymer RS, methacrylic acid copolymer L, methacrylic acid copolymer LD, and methacrylic acid copolymer S. Although mentioned, it is preferable to use aminoalkyl methacrylate copolymer E from the point of reduction of process decomposition products. Examples of the aminoalkyl methacrylate copolymer E include Eudragit E100 (Rohm GmbH & Co. KG) and Eudragit EPO (Rohm GmbH & Co. KG). The content of the acrylic polymer is preferably 0.05% by mass or more, more preferably 0.1% by mass or more, more preferably 0.5 to 20% by mass, particularly preferably 2 to 10% in the imidafenacin-containing granule. % By mass.

The intraoral quick-disintegrating tablet of the present invention is characterized by using granules obtained by granulating imidafenacin with one or more selected from the group consisting of tocopherol, a tocopherol derivative and an acrylic polymer.
Imidafenacin-containing granules can be easily produced by granulation methods such as dry granulation, agitation granulation, extrusion granulation, fluidized bed granulation, rolling fluidized bed granulation, spray granulation Can do. These granulation methods are obvious to those skilled in the art.
Preferred examples of the granulation method include a fluidized bed granulation method and a rolling fluidized bed granulation method. The average particle size of the granulated product is preferably 0.1 to 350 μm, more preferably 50 to 200 μm, when measured by the method described later.
The imidafenacin-containing granule can contain components other than tocopherol, a tocopherol derivative, and an acrylic polymer as long as the effects of the present invention are not significantly impaired. From the viewpoint of light stability, the excipient to be blended in the granulated product is preferably starch, more preferably partially pregelatinized starch.
Further, imidafenacin-containing granules can be dried after granulation from the viewpoint of the stability of pharmaceutical ingredients and the ease of production of tablets. The drying method is not particularly limited as long as it is a method that can be used for producing a pharmaceutical preparation.

Imidafenacin-containing granules are coated with a non-cellulosic coating agent for light stabilization. The non-cellulosic coating agent that can be used in the present invention may be a water-soluble coating agent, a hydrophobic coating agent, a gastric coating agent, or an enteric coating agent.
Suitable water-soluble coating agents include, for example, pH-independent coating agents such as povidone.
Suitable examples of the hydrophobic coating agent include stearyl alcohol and ammonio methacrylate copolymer.
Preferable examples of the gastric coating agent include aminoalkyl methacrylate copolymer E and polyvinyl acetal diethylaminoacetate.
As an enteric coating agent, a methacrylic acid copolymer (L, S) etc. are mentioned suitably.
The coating with these coating agents may be carried out together with iron sesquioxide or titanium oxide for the purpose of improving light stability. The content of the coating agent in the coated granules is not particularly limited, but is preferably pre-coated. For example, the amount is about 0.001 to 10 parts by mass, more preferably about 0.01 to 1 part by mass, and particularly preferably about 0.05 to 0.5 part by mass with respect to 1 part by mass of the granules.
Moreover, the coating method using a coating agent will not be specifically limited if it is a method which can be used for manufacture of a pharmaceutical formulation.

In the intraoral quick-disintegrating tablet of the present invention, an excipient and a disintegrant are used in combination with the coated imidafenacin-containing granule.
The excipient used here is not particularly limited as long as it can be used in the production of pharmaceutical preparations, and can be used as appropriate. As such an excipient, for example, those described in the Pharmaceutical Additives Encyclopedia [Japan Pharmaceutical Additives Association, Yakuji Nipposha (2007)] can be preferably used. For example, as the excipient, lactose, sugars such as glucose, sugar alcohols such as D-sorbitol, mannitol, celluloses such as crystalline cellulose, starches such as partially pregelatinized starch, and corn starch are preferably used. Can be mentioned. The excipient is preferably a sugar alcohol.

  The disintegrant used in the present invention is not particularly limited as long as it can be used for production of a pharmaceutical preparation, and various disintegrants can be used. As such a disintegrating agent, for example, those described in Pharmaceutical Additives Encyclopedia [Japan Pharmaceutical Additives Association, Yakuji Nipposha (2007)] can be used as appropriate. As the disintegrant, for example, carboxymethylcellulose calcium, celluloses such as low-substituted hydroxypropylcellulose, croscarmellose sodium, methylcellulose, crospovidone, etc. can be used, and rapid disintegration and easy drinking. It is preferable to use crospovidone from the viewpoint of (taste). 1-10 mass% is preferable in a tablet, and, as for the compounding quantity of a disintegrating agent, More preferably, it is 2-6 mass%.

  The intraoral quick-disintegrating tablet of the present invention can be blended with additives that can be used in the production of pharmaceutical preparations as necessary. Specifically, those described in the Pharmaceutical Additives Encyclopedia [Japan Pharmaceutical Additives Association, Yakuji Nipposha (2007)] can be used, for example, stearic acid and its metal salts as lubricants, talc, Light anhydrous silicic acid, hydrous silicon dioxide, sucrose fatty acid ester, etc., saccharides, sugar alcohols, aspartame, saccharin and salts thereof, glycyrrhizic acid and salts thereof, stevia, acesulfame potassium, etc. Sodium citrate, succinic acid, tartaric acid, fumaric acid, and the like, iron sesquioxide, yellow sesquioxide, caramel, riboflavin, aluminum lake, and the like as coloring agents, and menthol and orange oil as fragrances.

In the preparation of the intraoral rapidly disintegrating tablet of the present invention, the coated imidafenacin-containing granules are mixed with a composition containing an excipient and a disintegrant (components other than imidafenacin-containing granules). The amount of the composition containing the excipient and the disintegrant is, for example, 1 to 50 parts by mass, preferably 3 to 25 parts by mass with respect to 1 part by mass of the coated imidafenacin-containing granule.
Mixing of the coated imidafenacin-containing granule with a composition containing an excipient and a disintegrant can be performed, for example, in an apparatus such as a V-shaped mixer, a diamond mixer, or a drum mixer.
The mixture thus prepared is then compression molded to prepare the intraoral rapidly disintegrating tablet of the present invention.

The compression molding can be suitably performed with a tableting machine such as a rotary tableting machine. However, the shape of the intraoral quick disintegrating tablet of the present invention is not particularly limited as long as the effect of the present invention is not impaired. For example, special shapes such as hollows, polygons, and concave shapes can be used. In addition, a flat tablet with a thin tablet thickness and a large tablet diameter to increase the contact area of the tablet on the tongue, rapidly penetrate the oral cavity into the tablet, and increase the rapid disintegration of the oral cavity. It can also be formed into.
The pressure in compression molding is, for example, 300 to 2000 kg, preferably 600 to 1000 kg, and can be performed at room temperature and 60% RH.

Hereinafter, the present invention will be described more specifically with reference to examples, comparative examples and comparative tests of the present invention.

Evaluation method of imidafenacin-containing granulated product and coated granule [Particle size distribution measurement] Measured with sieve type particle size distribution measuring device (ATM, Sonic Shifter) using sieves with openings of 75, 106, 150, 180, 212, 355 μm did.
The average particle size (50% size) was calculated from the particle size distribution measurement.
Evaluation method of intraoral rapidly disintegrating tablet [Hardness test] The hardness was measured using a tablet hardness tester (Okada Seiko Co., Ltd.). The test is performed with 5 tablets, and the average value is shown.
[Disintegration test] Measured using a disintegration tester (manufactured by Toyama Sangyo Co., Ltd.). The test is performed with 6 tablets, and the average value is shown. The test solution was water, and the time until the tablet completely disintegrated and dissolved was measured.

Moreover, the additive used for an Example and a comparative example was shown below.
1． Product name Starch 1500G (Nihon Colorcon): Partially pregelatinized starch
2． Product name dl-α-Tocopherol (BASF)
3． Product name Eudragit EPO and E100 (Rohm GmbH & Co. KG): aminoalkyl methacrylate copolymer E
Four. Product name Kollidon 90F (BASF): Povidone
Five. Product name Magnesium stearate vegetable (Taihei Chemical Industry)
6． Product name Pairitol (ROQUETTE JAPAN): D-mannitol
7． Product name Kollidon CL-F (BASF): Crospovidone
8． Product name Carplex # 67 (DSL Japan): Hydrous silicon dioxide

Example 1
25.0 g of imidafenacin, 5.0 g of dl-α-tocopherol, and 12.5 g of Kollidon 90F (BASF) were dissolved in a mixed solution of 983.0 g of purified water and 1474.5 g of ethanol. 4957.5g of starch 1500G (Nihon Colorcon) was charged into a fluidized bed granulator (Freund Sangyo, FL-5), and this solution was coated by the top spray method (spraying liquid volume 75-85g / min, spraying air pressure 0 .3 MPa, supply air temperature 70 ° C.), and imidafenacin-containing granulated product was obtained (average particle size: 124 to 141 μm). Separately, 750 g of Eudragit EPO (Rohm GmbH & Co. KG) and 375 g of magnesium stearate plant (Taihei Chemical Industry) were dissolved in a mixed solution of 4550 g of purified water and 6825 g of ethanol. 3750 g of imidafenacin-containing granulated product was charged into a fluidized bed granulator (Freund Sangyo, FL-5), and this solution was coated by the top spray method (spraying liquid amount 75 to 85 g / min, spraying air pressure 0.3 MPa, (Air supply temperature 80 ° C.) and coating granules were obtained (average particle size: 101 to 104 μm).
Furthermore, after mixing 2600g of this coated granule, 14640g of Pearitol (ROQUETTE JAPAN), 540g of Kollidon CL-F (BASF) and 40g of Carplex # 67 (DSL Japan), 180g of magnesium stearate plant (Taihei Chemical Industry) was added and mixed. Thereafter, 180 mg tablets containing 0.1 mg imidafenacin per tablet were produced at a tableting pressure of 8.5 kN using a rotary tableting machine. The obtained tablet had a hardness of 4.7 kg (n = 5) and a disintegration time of 14 seconds (n = 6).

Example 2
25.0 g of imidafenacin, 125 g of Eudragit EPO (Rohm GmbH & Co. KG) and 62.5 g of magnesium stearate plant (Taihei Chemical Industry) were dissolved in a mixture of 915 g of purified water and 1372.5 g of ethanol. 4787.5g of starch 1500G (Nihon Colorcon) was charged into a fluidized bed granulator (Freund Sangyo, FL-5), and this solution was coated by the top spray method (spraying liquid amount 100g / min, spraying air pressure 0.3MPa) A supply temperature of 70 ° C.) and an imidafenacin-containing granulated product was obtained. Separately, 940 g of Eudragit EPO (Rohm GmbH & Co. KG) and 470 g of magnesium stearate plant (Taihei Chemical Industry) were dissolved in a mixed solution of 5702.8 g of purified water and 8554.2 g of ethanol. 4700 g of imidafenacin-containing granulated product is charged into a fluidized bed granulator (Freund Sangyo, FL-5), and this solution is coated by the top spray method (spraying liquid amount 100 g / min, spraying air pressure 0.3 MPa, air supply At a temperature of 80 ° C.) to obtain coated granules.
Furthermore, after mixing 2600g of this coated granule, 14640g of Pearitol (ROQUETTE JAPAN), 540g of Kollidon CL-F (BASF) and 40g of Carplex # 67 (DSL Japan), 180g of magnesium stearate plant (Taihei Chemical Industry) was added and mixed. Thereafter, 180 mg tablets containing 0.1 mg imidafenacin per tablet were produced at a tableting pressure of 8.6 kN using a rotary tableting machine. The obtained tablet had a hardness of 5.6 kg (n = 5) and a disintegration time of 12 seconds (n = 6).

Example 3
25.0 g of imidafenacin, 125 g of Eudragit EPO (Rohm GmbH & Co. KG) and 62.5 g of magnesium stearate plant (Taihei Chemical Industry) are dissolved in a mixture of 915 g of purified water and 1372.5 g of ethanol. 4787.5g of starch 1500G (Nihon Colorcon) was charged into a fluidized bed granulator (Freund Sangyo, FL-5), and this solution was coated by the top spray method (spraying liquid amount 100g / min, spraying air pressure 0.3MPa) , Supply temperature 70 ° C.), and imidafenacin-containing granulated product is obtained. Separately, 60 g of Eudragit RSPO (Rohm GmbH & Co. KG) and 30 g of magnesium stearate plant (Taihei Chemical Industry) are dissolved in a mixed solution of 91 g of purified water and 819 g of ethanol. 300 g of imidafenacin-containing granulated product is charged into a rolling fluidized bed granulator (Dalton, NQ-160), and this solution is coated by the side spray method (spraying liquid amount 20 g / min, spraying air pressure 0.15 MPa, supply (Air temperature 60 ° C.) and coated granules are obtained.
Furthermore, 78.0 g of this coated granule, 439.2 g of Pearitol (ROQUETTE JAPAN), 16.2 g of Kollidon CL-F (BASF) and 1.2 g of Carplex # 67 (DSL Japan) were mixed, and then the magnesium stearate plant ( Taihei Chemical Industry) After adding 5.4 g and mixing, 180 mg tablets containing 0.1 mg imidafenacin per tablet at a tableting pressure of 800 kg using a single tableting machine.

Example 4
25.0 g of imidafenacin, 125 g of Eudragit EPO (Rohm GmbH & Co. KG) and 62.5 g of magnesium stearate plant (Taihei Chemical Industry) are dissolved in a mixture of 915 g of purified water and 1372.5 g of ethanol. 4787.5g of starch 1500G (Nihon Colorcon) was charged into a fluidized bed granulator (Freund Sangyo, FL-5), and this solution was coated by the top spray method (spraying liquid amount 100g / min, spraying air pressure 0.3MPa) , Supply temperature 70 ° C.), and imidafenacin-containing granulated product is obtained. Separately, 60 g of AEA (Sankyo Lifetech) and 30 g of magnesium stearate plant (Taihei Chemical Industry) are dissolved in a mixed solution of 91 g of purified water and 819 g of ethanol. 300 g of imidafenacin-containing granulated product is charged into a rolling fluidized bed granulator (Dalton, NQ-160), and this solution is coated by the side spray method (spraying liquid amount 20 g / min, spraying air pressure 0.2 MPa, supply (Air temperature 60 ° C.) and coated granules are obtained.
Furthermore, 78.0 g of this coated granule, 439.2 g of Pearitol (ROQUETTE JAPAN), 16.2 g of Kollidon CL-F (BASF) and 1.2 g of Carplex # 67 (DSL Japan) were mixed, and then the magnesium stearate plant ( Taihei Chemical Industry) After adding 5.4 g and mixing, 180 mg tablets containing 0.1 mg imidafenacin per tablet at a tableting pressure of 800 kg using a single tableting machine.

Comparative Example 1
25.0 g of imidafenacin and 12.5 g of Kollidon 90F (BASF) were dissolved in a mixed solution of 738.75 g of purified water and 1723.75 g of ethanol. Starch 1500G (Nihon Colorcon) 4962.5g was charged into a fluidized bed granulator (Freund Sangyo, FL-5), and this solution was coated by the top spray method (spraying liquid amount 100g / min, spraying air pressure 0.3MPa) , Supply temperature 70 ° C.), and imidafenacin-containing granulated product was obtained (average particle size: 128 μm). Separately, 750 g of Eudragit EPO (Rohm GmbH & Co. KG) and 375 g of magnesium stearate plant (Taihei Chemical Industry) were dissolved in a mixture of 3412.5 g of purified water and 7962.5 g of ethanol. 3750 g of imidafenacin-containing granulated product was charged into a fluidized bed granulator (Freund Sangyo, FL-5), and this solution was coated by the top spray method (spraying liquid amount 100 g / min, spraying air pressure 0.3 MPa, air supply The temperature was 80 ° C.) to obtain coated granules (average particle size: 117 μm).
Furthermore, after mixing 2600g of this coated granule, 14640g of Pearitol (ROQUETTE JAPAN), 540g of Kollidon CL-F (BASF) and 40g of Carplex # 67 (DSL Japan), 180g of magnesium stearate plant (Taihei Chemical Industry) was added and mixed. Thereafter, 180 mg tablets containing 0.1 mg imidafenacin per tablet were produced at a tableting pressure of 9 kN using a rotary tableting machine. The obtained tablet had a hardness of 5.6 kg (n = 5) and a disintegration time of 12 seconds (n = 6).

Comparative Example 2
20.0 g of imidafenacin and 10.0 g of Kollidon 90F (BASF) were dissolved in a mixed solution of 591 g of purified water and 1379 g of ethanol. Charge 4970g of Starch 1500G (Nihon Colorcon) to a fluidized bed granulator (Freund Sangyo, FL-5), and coat this solution by the top spray method (spraying liquid amount 100g / min, spraying air pressure 0.3MPa, supply And an imidafenacin-containing granulated product was obtained (average particle size: 124 μm). Separately, 750 g of Eudragit EPO (Rohm GmbH & Co. KG) and 375 g of magnesium stearate plant (Taihei Chemical Industry) were dissolved in a mixture of 3412.5 g of purified water and 7962.5 g of ethanol. 3750 g of imidafenacin-containing granulated product was charged into a fluidized bed granulator (Freund Sangyo, FL-5), and this solution was coated by the top spray method (spraying liquid amount 100 g / min, spraying air pressure 0.3 MPa, air supply The temperature was 80 ° C.) to obtain coated granules (average particle size: 120 μm).
Further, 3250 g of this coated granule, 13990 g of Pairitol (ROQUETTE JAPAN), 540 g of Kollidon CL-F (BASF) and 40 g of Carplex # 67 (DSL Japan) were mixed, and then 180 g of magnesium stearate plant (Tahei Chemical Industry) was added and mixed. Thereafter, 180 mg tablets containing 0.1 mg imidafenacin per tablet were produced at a tableting pressure of 9 kN using a rotary tableting machine. The obtained tablet had a hardness of 4.9 kg (n = 5) and a disintegration time of 10 seconds (n = 6).

Comparative Example 3
16.7 g of imidafenacin and 8.3 g of Kollidon 90F (BASF) were dissolved in a mixture of 493.5 g of purified water and 1151.5 g of ethanol. Charge 4975 g of Starch 1500G (Nihon Colorcon) into a fluidized bed granulator (Freund Sangyo, FL-5), and coat this solution by the top spray method (spraying liquid amount 100 g / min, spraying air pressure 0.3 MPa, supply And an imidafenacin-containing granulated product was obtained (average particle size: 119 μm). Separately, 750 g of Eudragit EPO (Rohm GmbH & Co. KG) and 375 g of magnesium stearate plant (Taihei Chemical Industry) were dissolved in a mixture of 3412.5 g of purified water and 7962.5 g of ethanol. 3750 g of imidafenacin-containing granulated product was charged into a fluidized bed granulator (Freund Sangyo, FL-5), and this solution was coated by the top spray method (spraying liquid amount 100 g / min, spraying air pressure 0.3 MPa, air supply The temperature was 80 ° C.) to obtain coated granules (average particle size: 115 μm).
Furthermore, after mixing 3900g of this coated granule, 13340g of Pairitol (ROQUETTE JAPAN), 540g of Kollidon CL-F (BASF) and 40g of Carplex # 67 (DSL Japan), 180 g of magnesium stearate plant (Taihei Chemical Industry) was added and mixed. Thereafter, 180 mg tablets containing 0.1 mg imidafenacin per tablet were produced at a tableting pressure of 9 kN using a rotary tableting machine. The obtained tablet had a hardness of 5.2 kg (n = 5) and a disintegration time of 16 seconds (n = 6).

Test example 1
A purity test was performed on the imidafenacin-containing granules of Examples 1 and 2 and Comparative Examples 1 to 3. The results of the amount of imidafenacin-containing granules at the end of spraying, the end of drying, and the amount of degradation products of the coated granules are shown in Table 1. In addition, quantification of the decomposition product was evaluated by liquid chromatography (HPLC method).

HPLC method column: octadecylsilylated silica gel (average particle size 5 μm, inner diameter 4.6 mm × length 250 mm) (GL Sciences Inc., trade name Inertsil ODS-3)
Liquid A: Add diethylamine to diluted phosphoric acid (1 → 200) and adjust the pH to 6.0.
Liquid B: acetonitrile for liquid chromatography
Liquid C: Methanol solution for liquid chromatography: Concentration control is performed by changing the mixing ratio of liquid A, liquid B and liquid C.
Detector: UV
Measurement wavelength: 220 nm

From Table 1, the imidafenacin containing granule which does not mix | blend the dl- (alpha) -tocopherol etc. of the comparative examples 1-3 recognized the production | generation of the decomposition product. On the other hand, in the imidafenacin-containing granules blended with the dl-α-tocopherol of Example 1 and the imidafenacin-containing granules blended with the aminoalkyl methacrylate copolymer E of Example 2, almost no degradation products were observed.
From this result, it was confirmed that the process decomposition product at the time of granulation and coating was reduced by mix | blending a tocopherol and an acrylic polymer.

Reference example 1
4.0 g of imidafenacin and 2 g of Kollidon 90F (BASF) were dissolved in a mixture of 118.2 g of purified water and 275.8 g of ethanol. 394 g of starch 1500G (Nihon Colorcon) was charged into a rolling fluidized bed granulator (Dalton, NQ-160), and this solution was coated by the top spray method (spraying liquid amount 15 g / min, spraying air pressure 0.1 MPa, A supply temperature of 70 ° C.) and an imidafenacin-containing granulated product was obtained. Separately, 60 g of Eudragit EPO (Rohm GmbH & Co. KG) and 30 g of magnesium stearate plant (Taihei Chemical Industry) were dissolved in a mixture of 450 g of purified water and 1050 g of ethanol. 300 g of imidafenacin-containing granulated product is charged into a rolling fluidized bed granulator (Dalton, NQ-160), and this solution is coated by the top spray method (spraying liquid amount 20 g / min, spraying air pressure 0.15 MPa, supply (Gas temperature 80 ° C.) and coated granules were obtained.
Further, 5.2 g of this coated granule, 63.76 g of Pearitol (ROQUETTE JAPAN), 2.16 g of Kollidon CL-F (BASF) and 0.16 g of Carplex # 67 (DSL Japan) were mixed, and then the magnesium stearate plant ( Taihei Chemical Industry) After adding 0.72 g and mixing, 180 mg tablets containing 0.1 mg of imidafenacin per tablet were produced at a tableting pressure of 670 kg using a single tableting machine. The obtained tablet had a hardness of 5.1 kg (n = 5).

Reference example 2
4.0 g of imidafenacin and 2 g of Kollidon 90F (BASF) were dissolved in a mixed solution of 197 g of purified water and 197 g of ethanol. 394 g of starch 1500G (Nihon Colorcon) was charged into a rolling fluidized bed granulator (Dalton, NQ-160), and this solution was coated by the top spray method (spraying liquid amount 15 g / min, spraying air pressure 0.1 MPa, A supply temperature of 50 ° C.) and an imidafenacin-containing granulated product was obtained.
Further, 25 g of this imidafenacin-containing granulated product, 374.5 g of Pairitol (ROQUETTE JAPAN), 45 g of Polyplastidone XL-10 (ISP) and 1 g of Carplex # 67 (DSL Japan) were mixed and then mixed with magnesium stearate (Taipei). Chemical Industry) After adding 4.5 g and mixing, 180 mg tablets containing 0.1 mg of imidafenacin per tablet were produced at a tableting pressure of 800 kg using a rotary tableting machine. The obtained tablet had a hardness of 4.7 kg (n = 5).

Test example 2
A photostability test was performed on the preparations of Reference Examples 1 and 2. The amount of decomposition products in D65 lamp 4500 lux x about 12 days was measured. In addition, quantification of the decomposition product was evaluated by liquid chromatography (HPLC method).

HPLC method column: octadecylsilylated silica gel (average particle size 5 μm, inner diameter 4.6 mm × length 250 mm) (GL Sciences Inc., trade name Inertsil ODS-3)
Solution A: Diethylamine is added to diluted phosphoric acid (1 → 200) to adjust the pH to 6.0.
Liquid B: acetonitrile for liquid chromatography
Liquid C: Methanol solution for liquid chromatography: Concentration control is performed by changing the mixing ratio of liquid A, liquid B and liquid C.
Detector: UV
Measurement wavelength: 220 nm
The total degradation product of the tablet of Reference Example 1 was 0.07% before light irradiation, but was 0.4% after light irradiation. On the other hand, the total decomposition product of the tablet of Reference Example 2 was 0% before light irradiation, but was 3.1% after light irradiation.
From this result, it was confirmed that the light stability was improved by the coating of the non-cellulosic coating agent.

Claims (3)

Granules obtained by granulating basic polymer acrylic polymer with imidafenacin are coated with aminoalkyl methacrylate copolymer E, polyvinyl acetal diethylaminoacetate, povidone, methacrylic acid copolymer, stearyl alcohol, or ammonio methacrylate copolymer And fast-disintegrating in the oral cavity, characterized by compression molding. The intraoral quick-disintegrating tablet according to claim 1, wherein the acrylic polymer is an aminoalkyl methacrylate copolymer E. Granules obtained by granulating basic polymer acrylic polymer with imidafenacin are coated with aminoalkyl methacrylate copolymer E, polyvinyl acetal diethylaminoacetate, povidone, methacrylic acid copolymer, stearyl alcohol, or ammonio methacrylate copolymer Granules obtained by